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1630 Part XI: Malignant Lymphoid Diseases Chapter 98: Diffuse Large B-Cell Lymphoma and Related Diseases 1631

ROLE OF HIGH-DOSE CHEMOTHERAPY AND With a median followup of 76 months, the overall and EFSs were 17.5
AUTOLOGOUS STEM CELL TRANSPLANTATION and 7 months, respectively. In 33 patients with chemotherapy-sensitive,
aggressive disease who did not receive ASCT, EFS was 19 percent at
IN INITIAL THERAPY 36 months.
High-dose chemotherapy with autologous stem cell transplantation The addition of rituximab to the ifosfamide-carboplatin-etoposide
(ASCT) has been established as the standard of care for patients with (ICE) chemotherapy regimen (R-ICE) increased the CR rate of patients
relapsed, chemotherapy-sensitive aggressive lymphomas. However, the with relapsed or primary refractory DLBCL under consideration for
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role of ASCT as part of initial treatment remains very contentious. 69–76 ASCT. The CR rate was 53 percent, significantly better than the 27 per-
A recent phase III U.S. cooperative group study evaluated this question cent CR rate (p = 0.01) achieved among 147 similar, consecutive histor-
by enrolling 397 patients with high-intermediate and high-risk aggres- ical control patients with DLBCL treated with ICE. PFS for patients who
sive non-Hodgkin lymphoma who were treated with CHOP or R-CHOP underwent transplantation after R-ICE was marginally better than those
and then randomized responders (N = 253) to ASCT or further chemo- of 95 consecutive historical control patients who underwent transplan-
therapy alone. The ASCT group achieved superior PFS after 2 years tation after ICE (54 percent vs. 43 percent, P = 0.25).
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(69 percent vs. 55 percent for further chemotherapy, p = 0.005) but no A prospective study of 122 patients with relapsed and refractory
difference in OS was observed (74 percent vs. 71 percent, p = 0.3). In an DLBCL evaluated the role of etoposide, methylprednisolone, cytara-
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unplanned subgroup analysis, patients with high-risk DLBCL based on bine, and cisplatin (ESHAP). Forty-five patients (37 percent) attained
the IPI achieved superior PFS and OS with ASCT. a CR and 33 (27 percent) attained a PR, for a total response rate of
A meta-analysis evaluated the role of high-dose chemotherapy 64 percent. The median duration of CR was 20 months, with 28 percent
with ASCT as part of initial treatment. Fifteen randomized control tri- in CR at 3 years. The overall median survival duration was 14 months
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als including 3079 patients were eligible for this meta-analysis. Overall with an OS rate of 31 per cent after 3 years. Only 10 percent of all
treatment-related mortality was 6 percent in the ASCT group, which patients were alive and disease free after 40 months, however.
was not significantly different than with conventional chemotherapy. A randomized trial of second-line chemotherapy was published in
Thirteen studies including 2018 patients showed significantly higher 2010, comparing three cycles of either R-ICE or R-DHAP (rituximab,
CR rates in the group receiving ASCT (p = 0.004). However, ASCT did dexamethasone, high-dose cytarabine, and cisplatin) before planned
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not have an effect on OS, when compared to conventional chemother- ASCT. This study of 396 patients demonstrated no difference in terms
apy. Subgroup analysis of prognostic groups according to IPI did not of efficacy (response rate 64 percent vs. 63 percent) or survival (3-year
show any survival difference between ASCT and chemotherapy alone in OS 47 percent vs. 51 percent) with R-ICE or DHAP, respectively. In the
12 trials. EFS also showed no significant difference between ASCT and absence of high-level evidence supporting one salvage regimen over
conventional chemotherapy. another, treatment for relapsed/refractory DLBCL requires individual-
High-dose chemotherapy and ASCT is not routinely recom- ized consideration of comorbidities and patient factors.
mended as part of frontline therapy of DLBCL. Some authorities believe
that high-risk DLBCL patients who achieve at least a PR with firstline Autologous Stem Cell Transplantation
therapy may achieve superior outcomes if consolidated with ASCT, but The role of ASCT in relapsed DLBCL was demonstrated in a randomized
available data supporting this approach are flawed, preventing uniform trial of 109 patients who responded to salvage chemotherapy with the
adoption. Because abbreviated courses of chemotherapy prior to trans- DHAP chemotherapy regimen and were randomly assigned to receive
plantation impair outcomes, patients should receive a full course of four courses of chemotherapy plus radiotherapy (54 patients) or radio-
standard chemotherapy even if subsequent ASCT is planned. therapy plus intensive chemotherapy and ASCT (55 patients). After 5
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years, the EFS was 46 percent in the transplantation group and 12 per-
RECURRENT AND REFRACTORY DIFFUSE cent in the chemotherapy/radiotherapy group (p = 0.001), and the rate of
OS was 53 and 32 percent, respectively (p = 0.038). Patients with relapsed
LARGE B-CELL LYMPHOMA or primary refractory DLBCL who achieved CR before ASCT, had bet-
Chemotherapy ter outcomes than those who achieved only PR. Disease sensitivity at
Despite major advances in initial treatment of advanced DLBCL a sub- the time of ASCT and time from initial diagnosis to relapse remain key
stantial proportion of patients is either refractory to initial induction prognostic variables for predicting treatment outcome after standard
chemotherapy or relapses after chemotherapy. Relapse usually occurs ASCT. 86,87 Patients who undergo ASCT when the disease is resistant to
within the first 2 years after diagnosis, and the probability of long-term the initial induction therapy have less than a 20 percent probability of
survival among immunochemotherapy-treated patients who survive durable DFS.
2 years from DLBCL diagnosis without an event (relapse, retreatment,
or death) is similar to age-matched controls. Several second-line reg- Allogeneic Hematopoietic Stem Cell Transplantation
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imens have been evaluated in refractory and relapsed DLBCL with Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has
response rates of 50 to 70 percent, but none of these regimens has also been used in patients with DLBCL. The European Bone Marrow
distinguished itself as the preferred regimen. The use of single agents, Transplant Group performed a case-controlled study by matching 101
such as etoposide, cytarabine, mitoxantrone, lenalidomide, and allo-HSCT patients with 101 ASCT patients. The PFS was similar
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paclitaxel, result in response rates from 20 to 40 percent; however, in both types of transplants (49 percent for allo-HSCT vs. 46 percent
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responses to monotherapy are generally not long-lasting. for ASCT). The overall relapse and progression rate for the allo-H-
A prospective phase II study of EPOCH was examined in 131 SCT patients was 23 percent compared with 38 percent for the ASCT
patients with relapsed or resistant lymphoma. In 125 assessable patients. This difference was not statistically significant. Nine patients
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patients, 29 (23 percent) achieved complete responses and 60 (48 per- who had undergone ASCT died from early procedure-related toxicity
cent) achieved partial responses. Among 42 patients with resistant and 17 patients who had undergone allo-HSCT died from early pro-
disease, 57 percent responded, and in 28 patients with relapsed lym- cedure-related toxicity. To reduce the treatment-related mortality asso-
phomas, 89 percent responded with 54 percent complete responses. ciated with allo-HSCT, nonmyeloablative preparative regimens were

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